Open AccessThermoresponsive and Protease‐Cleavable Interferon‐Polypeptide Conjugates with Spatiotemporally Programmed Two‐Step Release Kinetics for Tumor Therapy
Author(s) -
Wang Zhuoran,
Guo Jianwen,
Sun Jiawei,
Liang Ping,
Wei Yan,
Deng Xuliang,
Gao Weiping
Publication year - 2019
Publication title -
advanced science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.388
H-Index - 100
ISSN - 2198-3844
DOI - 10.1002/advs.201900586
Subject(s) - conjugate , kinetics , chemistry , protease , biophysics , matrix metalloproteinase , melanoma , interferon , cancer research , biochemistry , enzyme , biology , immunology , mathematical analysis , physics , mathematics , quantum mechanics
Protein‐polymer conjugates show improved pharmacokinetics but reduced bioactivity and tumor penetration as compared to native proteins, resulting in limited antitumor efficacy. To address this dilemma, genetic engineering of a body temperature‐responsive and matrix metalloproteinase (MMP)‐cleavable conjugate of interferon alpha (IFNα) and elastin‐like polypeptide (ELP) is reported with spatiotemporally programmed two‐step release kinetics for tumor therapy. Notably, the conjugate could phase separate to form a depot postsubcutaneous injection, leading to 1‐month zero‐order release kinetics. Furthermore, it could selectively be cleaved by MMPs that are overexpressed in tumors to release IFNα from ELP and thus to recover the bioactivity of IFNα. Consequently, it exhibits dramatically enhanced tumor accumulation, tumor penetration, and antitumor efficacy as compared to free IFNα in two mouse models of melanoma and ovarian tumor. These findings may provide an intelligent technology of thermoresponsive and protease‐cleavable protein‐polymer conjugates with spatiotemporally programmed two‐step release kinetics for tumor treatment.